Upregulation of BDNF and hippocampal functions by a hippocampal ligand of PPARα
Dhruv Patel, Avik Roy, Sumita Raha, Madhuchhanda Kundu, Frank J. Gonzalez, Kalipada Pahan
Dhruv Patel, Avik Roy, Sumita Raha, Madhuchhanda Kundu, Frank J. Gonzalez, Kalipada Pahan
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Research Article Neuroscience

Upregulation of BDNF and hippocampal functions by a hippocampal ligand of PPARα

Abstract

Discovery strategies commonly focus on the identification of chemical libraries or natural products, but the modulation of endogenous ligands offers a much better therapeutic strategy due to their low adverse potential. Recently, we found that hexadecanamide (Hex) is present in hippocampal nuclei of normal mice as an endogenous ligand of PPARα. This study underlines the importance of Hex in inducing the expression of brain-derived neurotrophic factor (BDNF) from hippocampal neurons via PPARα. The level of Hex was lower in the hippocampi of 5XFAD mice as compared with that in non-Tg mice. Oral administration of Hex increased the level of this molecule in the hippocampus to stimulate BDNF and its downstream plasticity-associated molecules, promote synaptic functions in the hippocampus, and improve memory and learning in 5XFAD mice. However, oral Hex remained unable to stimulate hippocampal plasticity and improve cognitive behaviors in 5XFADPparα-null and 5XFADPparα-ΔHippo mice, indicating an essential role of hippocampal PPARα in Hex-mediated improvement in hippocampal functions. This is the first demonstration to our knowledge of protection of hippocampal functions by oral administration of a hippocampus-based drug, suggesting that Hex may be explored for therapeutic intervention in AD.

Authors

Dhruv Patel, Avik Roy, Sumita Raha, Madhuchhanda Kundu, Frank J. Gonzalez, Kalipada Pahan

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Figure 4

Hex upregulates BDNF in hippocampal neurons via PPARα.

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Hex upregulates BDNF in hippocampal neurons via PPARα. (A) WT or Pparα-n...
(A) WT or Pparα-null hippocampal neurons were treated with Hex (2 μM) for 5 hours followed by Bdnf mRNA by real-time PCR. Results are mean ± SD of 3 independent experiments. Statistical analyses between groups were performed using 2-way ANOVA considering genotype [F(1,8) = 7.918, P = 0.02] and treatment [F(1,8) = 6.919, P = 0.03] as 2 independent variables. Interaction statistics between 2 independent variables was calculated as well [F(1,8) = 7.918, P = 0.02]. Bonferroni’s multiple comparisons test was applied to assess the significance of the mean; **P < 0.01 vs. control, nsP > 0.05 vs. control. (B) Cells were also treated with Hex for 12 hours and BDNF protein level was investigated by immunostaining. Scale bars: 20 μm. (C) MFI of hippocampal BDNF. Statistical analyses were performed using 2-way ANOVA considering genotype [F(1,32) = 44.55, P < 0.001] and treatment [F(1,32) = 19.53, P < 0.001] as 2 independent variables. Interaction statistics between 2 independent variables was calculated as well [F(1,32) = 23.54, P < 0.001]. Bonferroni’s multiple comparisons test was applied to assess the significance of the mean; ***P < 0.001 vs. control, nsP > 0.05 vs. control. (D) Pparα-null hippocampal neurons were transduced with either empty lentiviral vector (GFP) or with the lentiviral vector containing flPPARα or Y464DPPARα for 48 hours followed by stimulation with Hex. After 5 hours, cells were analyzed for Bdnf mRNA. Results are mean ± SD of 3 independent experiments. Statistical analyses of Bdnf mRNA expression analyses between groups were performed using 2-way ANOVA considering lentiviral treatment [F(2,12) = 9.318, P = 0.004] and Hex treatment [F(1,12) = 11.71, P = 0.005] as 2 independent variables. Interaction statistics between 2 independent variables was calculated [F(2,12) = 9.318, P = 0.004]. Bonferroni’s multiple comparisons test was applied to assess the significance of the mean; ***P < 0.001 vs. control, nsP > 0.05 vs. control. Similarly, BDNF protein was analyzed by immunofluorescence. (E) Representative images. Scale bars: 20 μm. (F) MFI of hippocampal BDNF. Statistical analyses of hippocampal BDNF between groups were performed using 2-way ANOVA considering lentiviral treatment [F(2,48) = 23.31, P < 0.001] and Hex treatment [F(1,48) = 20.53, P < 0.001] as 2 independent variables.